US9469605B2 - Compounds and compositions for use a modulators of tau aggregation and alleviation of tauopathies - Google Patents
Compounds and compositions for use a modulators of tau aggregation and alleviation of tauopathies Download PDFInfo
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- US9469605B2 US9469605B2 US14/300,572 US201414300572A US9469605B2 US 9469605 B2 US9469605 B2 US 9469605B2 US 201414300572 A US201414300572 A US 201414300572A US 9469605 B2 US9469605 B2 US 9469605B2
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- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
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- C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
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- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
Definitions
- This invention relates to the use of bis- and tris-dihydroxyaryl compounds as well as sulfonamides, heteroaryls, tricycloalkyl and their analogs and pharmaceutically acceptable esters, and pharmaceutical compositions containing them, for modulation of tau aggregation and dissolution/disruption/inhibition of tau aggregates, and alleviation of tauopathies, such as Alzheimer's disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and familial frontotemporal dementia/Parkinsonism linked to chromosome 17 (FTDP-17), amyotrophic lateral sclerosis/Parkinsonism-dementia complex, argyrophilic grain dementia, dementia pugilistic, diffuse neurofibrillary tangles with calcification, progressive subcortical gliosis and tangle only dementia.
- AD Alzheimer's disease
- PiD Pick's disease
- PSP
- Tau is a microtubule associated protein found primarily in neuronal axons.
- Physiological phosphorylation of tau regulates the dynamics of the association of tau with tubulin, and thereby microtubule stability (Mazanetz. M. P. and Fischer, P. M. 2007. Nature Reviews 6:464-479).
- the stabilization of the microtubules in axons ensures that maintain their function for axonal transport, growth and branching (Bulic, B et al., 2009 Angew. Chem. Int. Ed. 48:2-15).
- Hyperphosphorylation and misfolding of the tau protein is thought to be the causative factor in abnormal intracellular aggregation leading ultimately to neuronal dysfunction. Protein aggregates have been found to be toxic to neurons.
- NFT's neurofibrillary tangles
- NT's neuropil threads
- argyrophilic dystrophic neurite plaques Brain, H and Braak, E, Neurobio. of Aging. 1997 18(4):351-357.
- PHF paired helical filaments
- Brain stages I-VI There are six stages (Braak stages I-VI) of tau deposition in the brain, which progress temporally at defined anatomical locations with the initial stages characterized primarily by the deposition of NFT's and NT's and the secondary stages further accompanied by NP (Braak, 1997).
- Braak's stages correlate well with clinical disease progression as demonstrated by increasing cognitive dysfunction. Severe cortical destruction which occurs around stages III-IV coincides with the first manifestations of the clinical onset of AD.
- no tau mutations have been identified in AD there is a strong correlation between NFT density and cognitive decline in AD (Bêtn, K. R., Trojanowski, J. Q., and Lee, V. M. 2009 Nature Reviews 8:783-93).
- Tau hyperphosphorylation is a common characteristic of a number of dementing disorders collectively known as tauopathies, some of which have disctinct tau pathology combined with other brain pathologies.
- Tauopathies include Alzheimer's disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and familial frontotemporal dementia/Parkinsonism linked to chromosome 17 (FTDP-17), amyotrophic lateral sclerosis/Parkinsonism-dementia complex, argyrophilic grain dementia, dementia pugilistic, diffuse neurofibrillary tangles with calcification, progressive subcortical gliosis and tangle only dementia.
- AD Alzheimer's disease
- PiD Pick's disease
- PSP progressive supranuclear palsy
- CBD corticobasal degeneration
- FTDP-17 familial frontotemporal dementia/Parkinsonism linked to chromosome 17
- tau pathology is typically limited to the neurons while other tauopathies can pathologically exhibit both neuronal and glial tau deposition (Higuchi, M, et al., 2002. Neuropsychopharmacology: The Fifth Generation of Progress, Chapter 94: Tau protein and tauopathy).
- tau protein may link Parkinson's and Alzheimer's disease (Shulman, J. M. and DeJager, P. L. 2009 Nature Genetics 41(12): 1261-1262). This study examined whether any genome wide association occurs between the two diseases and found that three genes and two new loci were linked to increased susceptibility.
- tau is a causative factor in disease but it is likely that either a loss or gain for function results in pathology.
- FTLD17 a missense mutation affects the alternative splicing of tau resulting in the disruption of the ratio of the 4R to 3R tau isoform. More of the 4R isoform with an extra repeat of the microtubule binding region may lead to overstabilization of the microtubules resulting in disease.
- Other post-translational events such as alterations in kinase activity and glycosylation could also cause hyperphosphorylation and result in disease or alternatively proteolytic cleavage could produce truncated tau products more inclined to aggregate (Bêtn, ibid).
- tau toxicity has been re-emphasized as an important therapeutic target in neurodegerative tauopathies (Keystone Symposium, March 2009). Routes for developing therapeutics are either directed to inhibiting tau-phosphorylation kinases or seeking compounds effective in the modulation of tau aggregation and/or the dissolution or disruption of tau aggregates which may prove equally useful or more specific for the alleviation of tauopathies (Rafii, M. and Aisen, P. 2009 BMC Medicine 7:7).
- a recent paper surveyed the efficacy of several classes of compounds for their ability to prevent tau aggregation and disaggregate pre-formed tau fibrils (Bulic et al.). Although there are general concerns regarding the toxicity of disassembled fibrils, Bulic et al., were able to show that reversing tau aggregation resulted in increased cell viability.
- this invention is bis- and tris-dihydroxyaryl compounds and their pharmaceutically acceptable esters, and pharmaceutically acceptable salts thereof for use in the modulation of tau aggregation and dissolution/disruption/inhibition of tau aggregates.
- the compounds are:
- R is a C 1 -C 10 alkylene group, in which, when the number of carbon atoms is at least 2, there are optionally 1 or 2 non-adjacent double bonds; 1 to 3 non-adjacent methylene groups are optionally replaced by NR′ (where R′ is H, alkyl, or acyl), O, or S; and 1 or 2 methylene groups are optionally replaced by a carbonyl or hydroxymethylene group; and (2) the compounds that are: 3,4,3′,4′-tetrahydroxybenzoin (compound DC-001); 3,4,3′,4′-tetrahydroxydesoxybenzoin (compound DC-002); 3,4,3′,4′-tetrahydroxydiphenylmethane (compound DC-003); 1,2-bis(3,4-dihydroxyphenyl)ethane (compound DC-004); 1,3-bis(3,4-dihydroxyphenyl)propane (compound DC-005); 3,4,3′,4′-
- R 1 and R 2 , and R 3 and R 4 are hydroxyl groups independently positioned at one of the positions selected from the group consisting of 2,3; 2,4; 2,5; 2,6; 3,5; 3,6; 4,5; 4,6 and 5,6, and R is selected from a sulfonamide, heteroaryl, tricycloalkyl and —C(I)NR′ where R′ is selected from H or CH 3 or pharmaceutically acceptable esters or salts thereof and compounds;
- this invention is a method of alleviating tauopathies in a mammal, especially a human, by administration of a therapeutically effective amount of a compound of the first aspect of this invention, for example as a pharmaceutical composition.
- this invention is the use of a compound of the first aspect of this invention in the manufacture of a medicament for allievating tauopathies.
- the chemicals within the specification will be typically be referred to by DC-##.
- the compounds of the invention are referred to generally as bis- and tris-dihydroxyaryl compounds, or sometimes just as “dihydroxyaryl compounds”. It will be noted that compound #84 has an additional hydroxy group, but does have two dihydroxyaryl groups; while compound #86 has only one dihydroxyaryl group but has an additional phenolic hydroxyl moiety.
- “Methylenedioxy analogs” refers to the compounds of this invention in which each of the pairs of adjacent hydroxyl moieties of the dihydroxyaryl groups have been replaced by methylenedioxy groups.
- the methylenedioxy compounds are illustrated and referred to as compounds #1B to #86B or DC-0001B to DC-0086B.
- the methylenedioxy groups also are convenient intermediate protecting groups for the dihydroxy moieties and therefore these disclosed compounds are believed to also serve as effective prodrugs.
- the methylenedioxy analogs #1B to #80B are illustrated in Example 30 of the parent application.
- “Pharmaceutically acceptable esters” refers to the compounds of this invention where the hydroxyl moieties of the dihydroxyaryl groups of the compounds are esterified with an acid or acids that result in a pharmaceutically acceptable poly(ester).
- the compounds are shown in Example 31 as acetylated, and these acetylated compounds are illustrated and referred to as compounds #1C to #86C or DC-0001C to DC-0086C; but it should be understood that the depiction of acetyl esters in Example 31 of the parent application, is merely illustrative, and all pharmaceutically acceptable esters are included within this invention.
- the ester groups are expected to serve as intermediate protecting groups for the hydroxyl moieties and therefore the pharmaceutically acceptable esters are expected to serve as effective prodrugs for their underlying bis- and tris-dihydroxyaryl compounds.
- “Mammal” includes both humans and non-human mammals, such as companion animals (cats, dogs, and the like), laboratory animals (such as mice, rats, guinea pigs, and the like) and farm animals (cattle, horses, sheep, goats, swine, and the like).
- “Pharmaceutically acceptable excipient” means an excipient that is conventionally useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and desirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. Such excipients may be solid, liquid, semisolid, or, in the case of an aerosol composition, gaseous.
- “Pharmaceutically acceptable salt” means a salt that is pharmaceutically acceptable and have the desired pharmacological properties. Such salts include salts that may be formed where acidic protons present in the compounds are capable of reacting with inorganic or organic bases. Suitable inorganic salts include those formed with the alkali metals, e.g. sodium and potassium, magnesium, calcium, and aluminum. Suitable organic salts include those formed with organic bases such as the amine bases, e.g. ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. Such salts also include acid addition salts formed with inorganic acids (e.g. hydrochloric and hydrobromic acids) and organic acids (e.g.
- a pharmaceutically acceptable salt may be a mono-acid-mono-salt or a di-salt; and similarly where there are more than two acidic groups present, some or all of such groups can be salified.
- a “therapeutically effective amount” in general means the amount that, when administered to a subject or animal for alleviating a disease, and is sufficient to affect the desired degree of treatment for the disease or reduce or diminish pathological hallmarks associated with the disease. For example, reducing tau aggregates associated with Alzheimer's disease or another tauopathy.
- a “therapeutically effective amount” or a “therapeutically effective dosage” preferably modulates or inhibits, causes dissolution, and/or disrupts, abnormal tau aggregation, or contributes towards the treatment of a disease associated with these conditions, such as Alzheimer's disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and familial frontotemporal dementia/Parkinsonism linked to chromosome 17 (FTDP-17), amyotrophic lateral sclerosis/Parkinsonism-dementia complex, argyrophilic grain dementia, dementia pugilistic, diffuse neurofibrillary tangles with calcification, progressive subcortical gliosis and tangle only dementia.
- AD Alzheimer's disease
- PiD Pick's disease
- PSP progressive supranuclear palsy
- CBD corticobasal degeneration
- FTDP-17 familial frontotemporal dementia/Parkinsonism linked to
- Effective amounts of a compound of this invention or composition thereof for treatment of a mammalian subject are about 0.1 to about 1000 mg/Kg of body weight of the subject/day, such as from about 1 to about 100 mg/Kg/day, especially from about 10 to about 100 mg/Kg/day.
- a broad range of disclosed composition dosages are believed to be both safe and effective.
- Treating” or “treatment” of a disease in general means modulating tau aggregation or the dissolution, disruption, and/or inhibition of abnormal tau aggregates associated with a tauopathy.
- a pharmaceutical agent or “pharmacological agent” or “pharmaceutical composition” refers to a compound or combination of compounds used for treatment, preferably in a pure or near pure form.
- pharmaceutical or pharmacological agents include the compounds of this invention.
- the compounds are desirably purified to 80% homogeneity, and preferably to 90% homogeneity. Compounds and compositions purified to 99.9% homogeneity are believed to be advantageous. As a test or confirmation, a suitable homogeneous compound on HPLC would yield what those skilled in the art would identify as a single sharp-peak band.
- R is a C 1 -C 10 alkylene group, in which, when the number of carbon atoms is at least 2, there are optionally 1 or 2 non-adjacent double bonds; 1 to 3 non-adjacent methylene groups are optionally replaced by NR′ (where R′ is H, alkyl, or acyl), O, or S; and 1 or 2 methylene groups are optionally replaced by a carbonyl or hydroxymethylene group; and (2) the compounds that are: 3,4,3′,4′-tetrahydroxybenzoin (compound DC-001); 3,4,3′,4′-tetrahydroxydesoxybenzoin (compound DC-002); 3,4,3′,4′-tetrahydroxydiphenylmethane (compound DC-003); 1,2-bis(3,4-dihydroxyphenyl)ethane (compound DC-004); 1,3-bis(3,4-dihydroxyphenyl)propane (compound DC-005); 3,4,3′,4′-
- R 1 and R 2 , and R 3 and R 4 are hydroxyl groups independently positioned at one of the positions selected from the group consisting of 2,3; 2,4; 2,5; 2,6; 3,5; 3,6; 4,5; 4,6 and 5,6, and R is selected from a sulfonamide, heteroaryl, tricycloalkyl and —C(O)NR′ where R′ is selected from H or CH 3 or pharmaceutically acceptable esters or salts thereof.
- the compounds of this invention for use are also:
- the compounds of this invention may be prepared by methods generally known to the person of ordinary skill in the art, having regard to that knowledge and the disclosure of this application and its priority applications, the contents of which are incorporated by reference.
- the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as the Aldrich Chemical Company (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma (St. Louis, Mo.), or Lancaster Synthesis Inc. (Windham, N.H.) or are prepared by methods well known to a person of ordinary skill in the art, following procedures described in such references as Fieser and Fieser's Reagents for Organic Synthesis , vols. 1-17, John Wiley and Sons, New York, N.Y., 1991 ; Rodd's Chemistry of Carbon Compounds , vols. 1-5 and supps., Elsevier Science Publishers, 1989; Organic Reactions, vols.
- the starting materials, intermediates, and compounds of this invention may be isolated and purified using conventional techniques, including precipitation, filtration, distillation, crystallization, chromatography, and the like.
- the compounds may be characterized using conventional methods, including physical constants and spectroscopic methods.
- the compounds of this invention either as the dihydroxyaryl compounds per se, or as the methylenedioxy analogs or pharmaceutically acceptable esters (once de-protected either in the body or in vitro), or the compounds set out herein to modulate tau aggregation or to cause the dissolution, disruption and/or inhibition of tau aggregates and for alleviating tauopathies.
- Their activity can be measured in vitro by methods such as those discussed in Example 1, while their activity in vivo against tauopathies can be measured in animal models, such as those transgenic mouse models that mimic AD and other tauopathies, and in humans (Dickey, C et al., 2009 ⁇ m J Pathol.
- “Tauopathies” suitable for alleviation with the compounds of this invention are diseases associated with abnormal tau aggregation are Alzheimer's disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and familial frontotemporal dementia/Parkinsonism linked to chromosome 17 (FTDP-17), amyotrophic lateral sclerosis/Parkinsonism-dementia complex, argyrophilic grain dementia, dementia pugilistic, diffuse neurofibrillary tangles with calcification, progressive subcortical gliosis and tangle only dementia.
- AD Alzheimer's disease
- PiD Pick's disease
- PSP progressive supranuclear palsy
- CBD corticobasal degeneration
- FTDP-17 familial frontotemporal dementia/Parkinsonism linked to chromosome 17
- FTDP-17 familial frontotemporal dementia/Parkinsonism linked to chromosome 17
- compounds of the invention will be administered in therapeutically effective amounts by any of the usual modes known in the art, either singly or in combination with at least one other compound of this invention and/or at least one other conventional therapeutic agent for the disease being treated.
- a therapeutically effective amount may vary widely depending on the disease, its severity, the age and relative health of the animal being treated, the potency of the compound(s), and other factors.
- tau protein modulators or aggregation inhibitors therapeutically effective amounts of compounds of this invention may range from 0.1-1000 mg/Kg body weight/day, such as from 1-100 mg/Kg/day; for example, 10-100 mg/Kg/day.
- a person of ordinary skill in the art will be conventionally able, and without undue experimentation, having regard to that skill and to this disclosure, to determine a therapeutically effective amount of a compound for the alleviation of tau aggregation or tauopathy.
- compositions will contain a compound of this invention that is at least substantially pure.
- pure means better than 95% pure
- substantially pure means a compound synthesized such that the compound, as made as available for consideration into a therapeutic dosage, has only those impurities that can not readily nor reasonably be removed by conventional purification processes.
- compositions will be administered as pharmaceutical compositions by one of the following routes: oral, topical, systemic (e.g. transdermal, intranasal, or by suppository), or parenteral (e.g. intramuscular, subcutaneous, or intravenous injection).
- routes e.g. oral, topical, systemic (e.g. transdermal, intranasal, or by suppository), or parenteral (e.g. intramuscular, subcutaneous, or intravenous injection).
- routes e.g. intramuscular, subcutaneous, or intravenous injection.
- Compositions may take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions; and comprise at least one compound of this invention in combination with at least one pharmaceutically acceptable excipient.
- Suitable excipients are well known to persons of ordinary skill in the art, and they, and the methods of formulating the compositions, may be found in such standard references as Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, Pa.
- Suitable liquid carriers, especially for injectable solutions include water, aqueous saline solution, aqueous dextrose solution, and glycols.
- Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
- Tablets contain the compound in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets.
- excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, maize starch or alginic acid; binding agents, for example, maize starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate or stearic acid or tale.
- the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a time delay material such as glycerol monostearate or glycerol distearate may be employed.
- Formulations for oral use may also be presented as hard gelatin capsules wherein the compound is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
- Aqueous suspensions contain the compound in admixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be naturally occurring phosphatides, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids such as hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters from fatty acids and a hexitol anhydrides, for example, polyethylene sorbitan monooleate.
- the aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, or one or more sweetening agents, such as sucrose or saccharin.
- preservatives for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, or one or more sweetening agents, such as sucrose or saccharin.
- Oily suspensions may be formulated by suspending the compound in a vegetable oil, for example arachis oil, olive oil, sesame oil, or coconut oil or in a mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
- Sweetening agents, such as those set forth below, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already described above. Additional excipients, for example sweetening, flavoring and agents, may also be present.
- the compounds of the invention may also be in the form of oil-in-water emulsions.
- the oily phase may be a vegetable oil, for example olive oil or arachis oils, or a mineral oil, for example liquid paraffin or mixtures of these.
- Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soy bean, lecithin, and occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
- the emulsion may also contain sweetening and flavoring agents.
- Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, sorbitol or sucrose.
- Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
- the compounds of the invention can also be administered by injection or infusion, either subcutaneously or intravenously, or intramuscularly, or intrasternally, or intranasally, or by infusion techniques in the form of sterile injectable or oleaginous suspension.
- the compound may be in the form of a sterile injectable aqueous or oleaginous suspensions. These suspensions may be formulated according to the known art using suitable dispersing of wetting agents and suspending agents that have been described above.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent for example, as a solution in 1,3-butanediol.
- Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oils may be conventionally employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid find use in the preparation of injectables. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, several divided dosages may be administered daily or the dosage may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
- Dosage unit form refers to physically discrete units suited as unitary dosages for the subjects to be treated; each containing a therapeutically effective quantity of the compound and at least one pharmaceutical excipient.
- a drug product will comprise a dosage unit form within a container that is labeled or accompanied by a label indicating the intended method of treatment, such as the treatment of a tauopathy or disease associated with abnormal tau aggregation.
- the invention also includes the use of sustained release formulations to deliver the compounds of the present invention to the desired target (i.e. brain or systemic organs) at high circulating levels (between 10 ⁇ 9 and 10 ⁇ 4 M) are also disclosed.
- the circulating levels of the compounds is maintained up to 10 ⁇ 7 M.
- the levels are either circulating in the patient systemically, or in a preferred embodiment, present in brain tissue, and in a most preferred embodiment, localized to the areas of abnormal tau aggregation.
- the invention includes a unique feature of administration comprising a sustained release formulation so that a constant level of therapeutic compound is maintained between 10 ⁇ 8 and 10 ⁇ 6 M between 48 to 96 hours in the sera.
- sustained and/or timed release formulations may be made by sustained release means of delivery devices that are well known to those of ordinary skill in the art, such as those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 4,710,384; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556 and 5,733,566, the disclosures of which are each incorporated herein by reference.
- compositions can be used to provide slow or sustained release of one or more of the active compounds using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or the like.
- sustained release formulations known to those skilled in the art, including those described herein, may be readily selected for use with the pharmaceutical compositions of the invention.
- single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, caplets, powders and the like, that are adapted for sustained release are encompassed by the present invention.
- the sustained release formulation contains active compound such as, but not limited to, microcrystalline cellulose, maltodextrin, ethylcellulose, and magnesium stearate.
- active compound such as, but not limited to, microcrystalline cellulose, maltodextrin, ethylcellulose, and magnesium stearate.
- the sustained release formulation is encapsulated by coating particles or granules of the pharmaceutical composition of the invention with varying thickness of slowly soluble polymers or by microencapsulation.
- the sustained release formulation is encapsulated with a coating material of varying thickness (e.g. about 1 micron to 200 microns) that allow the dissolution of the pharmaceutical composition about 48 hours to about 72 hours after administration to a mammal.
- the coating material is a food-approved additive.
- the sustained release formulation is a matrix dissolution device that is prepared by compressing the drug with a slowly soluble polymer carrier into a tablet.
- the coated particles have a size range between about 0.1 to about 300 microns, as disclosed in U.S. Pat. Nos. 4,710,384 and 5,354,556, which are incorporated herein by reference in their entireties.
- Each of the particles is in the form of a micromatrix, with the active ingredient uniformly distributed throughout the polymer.
- Sustained release formulations such as those described in U.S. Pat. No. 4,710,384, which is incorporated herein by reference in its entirety, having a relatively high percentage of plasticizer in the coating in order to permit sufficient flexibility to prevent substantial breakage during compression are disclosed.
- the specific amount of plasticizer varies depending on the nature of the coating and the particular plasticizer used. The amount may be readily determined empirically by testing the release characteristics of the tablets formed. If the medicament is released too quickly, then more plasticizer is used. Release characteristics are also a function of the thickness of the coating. When substantial amounts of plasticizer are used, the sustained release capacity of the coating diminishes. Thus, the thickness of the coating may be increased slightly to make up for an increase in the amount of plasticizer.
- the plasticizer in such an embodiment will be present in an amount of about 15 to 30% of the sustained release material in the coating, preferably 20 to 25%, and the amount of coating will be from 10 to 25% of the weight of the active material, preferably 15 to 20%. Any conventional pharmaceutically acceptable plasticizer may be incorporated into the coating.
- the compounds of the invention can be formulated as a sustained and/or timed release formulation. All sustained release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-sustained counterparts. Ideally, the use of an optimally designed sustained release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition. Advantages of sustained release formulations may include: 1) extended activity of the composition, 2) reduced dosage frequency, and 3) increased patient compliance. In addition, sustained release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the composition, and thus can affect the occurrence of side effects.
- the sustained release formulations of the invention are designed to initially release an amount of the therapeutic composition that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of compositions to maintain this level of therapeutic effect over an extended period of time.
- the therapeutic composition In order to maintain this constant level in the body, the therapeutic composition must be released from the dosage form at a rate that will replace the composition being metabolized and excreted from the body.
- sustained release of an active ingredient may be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds.
- sustained release component in the context of the present invention is defined herein as a compound or compounds, including, but not limited to, polymers, polymer matrices, gels, permeable membranes, liposomes, microspheres, or the like, or a combination thereof, that facilitates the sustained release of the active ingredient.
- the complex may be formulated in an appropriate buffer, for example, phosphate buffered saline, or other physiologically compatible solutions.
- an appropriate buffer for example, phosphate buffered saline, or other physiologically compatible solutions.
- the resulting complex may be formulated with a non-ionic surfactant such as Tween, or polyethylene glycol.
- the compounds and their physiologically solvents may be formulated for administration by inhalation or insufflation (either through the mouth or the nose) or oral, buccal, parenteral, or rectal administration, as examples.
- Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
- the compounds of the present invention are formulated as controlled release powders of discrete microparticles that can be readily formulated in liquid form.
- the sustained release powder comprises particles containing an active ingredient and optionally, an excipient with at least one non-toxic polymer.
- the powder can be dispersed or suspended in a liquid vehicle and will maintain its sustained release characteristics for a useful period of time. These dispersions or suspensions have both chemical stability and stability in terms of dissolution rate.
- the powder may contain an excipient comprising a polymer, which may be soluble, insoluble, permeable, impermeable, or biodegradable.
- the polymers may be polymers or copolymers.
- the polymer may be a natural or synthetic polymer. Natural polymers include polypeptides (e.g., zein), polysaccharides (e.g., cellulose), and alginic acid. Representative synthetic polymers include those described, but not limited to, those described in column 3, lines 33-45 of U.S. Pat. No.
- the sustained release compounds of the invention may be formulated for parenteral administration, e.g., by intramuscular injections or implants for subcutaneous tissues and various body cavities and transdermal devices.
- intramuscular injections are formulated as aqueous or oil suspensions.
- the sustained release effect is due to, in part, a reduction in solubility of the active compound upon complexation or a decrease in dissolution rate.
- oil suspensions and solutions wherein the release rate of an active compound is determined by partitioning of the active compound out of the oil into the surrounding aqueous medium. Only active compounds which are oil soluble and have the desired partition characteristics are suitable.
- Oils that may be used for intramuscular injection include, but are not limited to, sesame, olive, arachis, maize, almond, soybean, cottonseed and castor oil.
- a highly developed form of drug delivery that imparts sustained release over periods of time ranging from days to years is to implant a drug-bearing polymeric device subcutaneously or in various body cavities.
- the polymer material used in an implant which must be biocompatible and nontoxic, include but are not limited to hydrogels, silicones, polyethylenes, ethylene-vinyl acetate copolymers, or biodegradable polymers.
- the compounds set out above were found to be potent in the dissolution/disruption/inhibition of Tau tangles or Tau aggregates.
- the efficacy of the compounds to cause a dissolution/disassembly/disruption of pre-formed Tau aggregates was analyzed.
- Thioflavin T fluorometry was used in this study to determine the effects of the compounds compared to a negative control peptide.
- Thioflavin T binds specifically to aggregated Tau or Tau tangles, and this binding produces a fluorescence enhancement at 485 nm that is directly proportional to the amount of aggregated Tau. The higher the fluorescence, the greater the amount of aggregated Tau.
- Tau-441 was pre-fibrillized or aggregated by combining with Heparin (SIGMA) at 1:1 wt/wt, then incubation at 37° C. and shaking at 1400 rpm for 8 days. Following the pre-fibrillization, 30 ⁇ g of aggregated Tau-441 (rPeptide) was then incubated at 37° C. for 3 days either alone, or in the presence of one of the compounds or negative control (at Tau:test compound weight ratios of 1:1, 1:0.1, 1:0.01 or 1:0.001).
- each incubation mixture was transferred into a 96-well microtiter plate containing 150 ⁇ l of distilled water and 50 ⁇ l of a Thioflavin T solution (i.e. 500 mM Thioflavin T in 250 mM phosphate buffer, pH 6.8).
- the fluorescence was read at 485 nm (444 nm excitation wavelength) using an ELISA plate fluorometer after subtraction with buffer alone or compound alone, as blank.
- DC-51-W2 caused a significant (p ⁇ 0.01) 92.4 ⁇ 1.23% dissolution/disruption/inhibition when used at a Tau:test compound wt/wt ratio of 1:0.1, and a 74.0 ⁇ 4.01% dissolution/disruption/inhibition when used at a Tau:compound wt/wt ratio of 1:0.01.
- compound DC-004 caused a 92.8 ⁇ 2.59% dissolution/disruption/inhibition, and a 68.0 ⁇ 1.71% dissolution/disruption/inhibition when used at a Tau:compound wt/wt ratio of 1:0.01.
- TauRD Tau Repeat Domains
- Tetracycline-inducible mammalian expression constructs pcDNA4/TO-TauRD, were generated by insertion of cDNA fragments encoding the human tau repeat domain (TauRD; amino acid residues 244-372 in REFSEQ mRNA ENST00000351559) into pcDNATM4/TO vector (Invitrogen).
- the vector allows tetracycline-regulated expression of the gene of interest in mammalian host cells when a pcDNATM6/TR construct (Invitrogen) is also co-expressed.
- the wild type TauRD (TauRDWT) cDNA insert was amplified from human brain single stranded cDNA by PCR with a forward primer (Tau6+730F), overlapped with the cDNA sequences of residues 244-249, and a reverse primer (Tau1116+3R) overlapped with residues 364-372 of human tau (REFSEQ mRNA ENST00000351559).
- the PCR products were first cloned into a pDrive-UA cloning vector (QIAGEN; Valencia, Calif., USA) as instructed by the manufacturer to generate pDrive-TauRDWT.
- Mutant constructs that contain mutations of AK280, P301S, and P301L found in frontotemporal dementia with Parkinsonism-17 were made on the pDrive-TauRDWT backbone using a QuikChange® Site-Directed Mutagenesis Kit (Stratagene, La Jolla, Calif.), as instructed by the manufacturer. The mutations have been shown to increase Tau aggregations in vitro or in vivo (Blaken et al., 2009).
- the cDNA inserts in pDrive-TauRDWT, pDrive-TauRD ⁇ K280, pDrive-TauRDP301S and pDrive-TauRDP301L were then released by EcoRI digestion of the plasmids, gel-purified with a gel extraction kit (QIAGEN) as instructed, and subcloned into a pcDNATM4/TO vector at EcoRI sites to generate pcDNA4/TO-TauRDWT, pcDNA4/TO-TauRD ⁇ K280, pcDNA4/TO-TauRDP301S, and pcDNA4/TO-TauRDP301L expression constructs.
- QIAGEN gel extraction kit
- the pcDNA4/TO-TauRD constructs are driven by a hybrid promoter consisting of the human cytomegalovirus immediate-early promoter and tetracycline operator 2 sites for high-level tetracycline-regulated expression in mammalian cells.
- a hybrid promoter consisting of the human cytomegalovirus immediate-early promoter and tetracycline operator 2 sites for high-level tetracycline-regulated expression in mammalian cells.
- Tet repressor homodimers expressed from pcDNATM6/TR
- Addition of tetracycline to the cells de-represses the hybrid promoter in pcDNATM4/TO, and allows expression of TauRD.
- Tetracycline-inducible cell lines stably transfected with pcDNA4/TO-TauRDWT, pcDNA4/TO-TauRD ⁇ K280, pcDNA4/TO-TauRDP301S, and pcDNA4/TO-TauRDP301L were generated to assess TauRD aggregation in cell culture.
- TRExTM-293 cells Invitrogen; R710-07), modified human embryonic kidney 293 cells (ATCC; CRL-1573) by stable transfection of pcDNATM6/TR, were employed to generate the TauRD stable cell lines.
- Both parental cells (TRExTM-293 cells) and their derivatives (TREx293-TauRD) (see below) were maintained in culture media supplemented with 5 ⁇ g/ml blasticidin for selection of pcDNA6/TR-containing cells.
- Cells were routinely cultured in a regular growth media (RGM) that contained Dulbecco's Modified Eagle Medium (DMEM) (Invitrogen) supplemented with 10% fetal bovine serum, penicillin (60 units/mL), streptomycin (60 ⁇ g/mL) and blasticidin (5 ⁇ g/ml) at 37° C. in a cell culture incubator supplemented with 5% CO 2 .
- RGM regular growth media
- DMEM Dulbecco's Modified Eagle Medium
- penicillin 60 units/mL
- streptomycin 60 ⁇ g/mL
- blasticidin 5 ⁇ g/ml
- TRExTM-293 cells were grown to 70-80% confluence in 12-well plates, and transfected with 1.2 g of pcDNA4/TO-TauRDWT, pcDNA4/TO-TauRDAK280, pcDNA4/TO-TauRDP301S, or pcDNA4/TO-TauRDP301L. Transfection was mediated by polyethylenimines (Polysciences, Inc.) as described by Hu et al. (2005 JBC 280(13):12548-58).
- TRExTM-293 cells stably transfected with various pcDNA4/TO-TauRD constructs are referred as TREx293-TauRDWT, TREx293-TauRD ⁇ K280, TREx293-TauRDP301S, and TREx293-TauRDP301L cells.
- Soluble/insoluble TauRD monomers and oligomers in lysates were prepared and analyzed as follows.
- TREx293-TauRDWT (clone B1) cells were grown in RGM supplemented with 0.4 mg/ml of Zeocin, 1 g/ml of tetracycline (Tet+), and with or without addition of compounds for 2 days. Cells were gently washed once with PBS, and were lysed in a cold lysis buffer 50 mM Tris-HCl, pH 7.5, 100 mM NaCl, and 0.5% Triton X-100, supplemented with CompleteTM protease inhibitor cocktail tablets (Roche) at one tablet/25 ml lysis buffer on ice for 20 min.
- CompleteTM protease inhibitor cocktail tablets (Roche) at one tablet/25 ml lysis buffer on ice for 20 min.
- Cell lysates were collected with cell scrapers into centrifuge tubes, and centrifuged at 15,000 ⁇ g at 4° C. for 15 min. The supernatants were collected as soluble fractions. Pellets were then dissolved in non-reduced 1 ⁇ Laemmli buffer [2% sodium dodecyl sulfate (SDS), 10% glycerol, 0.002% bromphenol blue, 62.5 mM Tris HCl, pH 6.8] by shaking at 24° C. for 50 min, boiling for 5 min, and centrifuging at 15,000 ⁇ g at 4° C. for 15 min. The supernatants were collected as insoluble fractions and were directly loaded on Western gels; the soluble fractions were diluted at 3:1 in 4 ⁇ non-reduced Laemmli buffer before loading on Western gels.
- SDS sodium dodecyl sulfate
- Soluble/insoluble fractions of cell lysates were separated in 4-12% Bis/Tris Criterion XT gels (Bio-Rad) at 180 volts, with buffer systems recommended by the manufacturer. After electrophoresis, protein bands were transferred onto Immobilon-PSQ membranes in a tris/glycine transfer buffer (Bio-Rad) using Bio-Rad CriterionTM Blotters. The transfer was conducted at 0.25 A (constant) for 60 min at 4° C.
- membranes were stripped with a RestoreTM Western blot stripping buffer (Thermo Scientific; Rockford, Ill.), and re-probed with mouse anti- ⁇ -tubulin (1:30,000) (Sigma; Saint Louis, Mo.), and/or anti- ⁇ -actin (1:200,000) (Chemicon International) monoclonal antibodies. Quantitation of relative intensities of protein bands on autoradiographic films was performed by image quantification with the ScionImage software (http://www.scioncorp.com) as instructed in the product manual.
- TREx293-TauRDWT clone B1 cells were plated in 12-well culture plates with RGM, supplemented with 0.4 mg/ml of Zeocin. The plating density was optimized to reach 25-30% of confluence on next day. On the next day, cell culture media was replaced with 1 ml per well of RGM (eliminating blasticidin) supplemented with 1 g/ml of tetracycline (Tet+), and freshly-diluted test compounds at the final concentrations between 0.25-100 ⁇ M.
- RGM eliminating blasticidin
- Tet+ tetracycline
- FIG. 1 of the priority application shows that compound DC-51 and its analogs modulate levels of TauRD oligomers and monomers in insoluble fractions of TREx293-TauRDWT (clone B1) cell cultures as assessed by Western analysis.
- TREx293-TauRDWT cells were treated with DMSO vehicle control (Lanes 2, 15 and 28 of FIG. 1 of the priority application (U.S. Pat. No.
- insoluble fractions of cell lysates were collected as described, and analyzed by Western analysis with a rabbit anti-human Tau antibody (FIG. 1A of the priority application (U.S. Pat. No. 8,455,867)), and then re-probed for ⁇ -tubulin as a soluble protein marker and a protein loading control (FIG. 1B of the priority application (U.S. Pat. No. 8,455,867)). Lysates of cells grown in the absence of tetracycline (Lanes 1; no TauRD expression) were also analyzed in parallel to show background bands derived from endogenous Tau.
- Lanes 1 no TauRD expression
- FIG. 2 of the priority application shows that compound DC-51 and its analogs modulate levels of TauRD oligomers and monomers in soluble fractions of TREx293-TauRDWT (clone B1) cell cultures as assessed by Western analysis.
- TREx293-TauRDWT cells were treated with DMSO vehicle control (Lanes 2, 15 and 28), compound DC-51 (0.5 ⁇ M in lanes 9&12; 1 ⁇ M in lanes 10&13; ⁇ M in lanes 11&14) and its analogs DC-51-W3 (10 ⁇ M in lanes 16&19; 40 ⁇ M in lanes 17&20; 80 ⁇ M in lanes 18&21), and DC-51-W4 (10 ⁇ M in lanes 22&25; 40 ⁇ M in lanes 23&26; 80 ⁇ M in lanes 24&27) in 12-well plates for 48 hrs (compound-containing fresh media were every 24 hrs). Each condition was in duplicate.
- soluble fractions of cell lysates were collected as described, and analyzed by Western analysis with a rabbit anti-human Tau antibody (FIG. 2A of the priority application (U.S. Pat. No. 8,455,867)), and then re-probed for ⁇ -tubulin as a soluble protein marker and a protein loading control (FIG. 2B of the priority application (U.S. Pat. No. 8,455,867)). Lysates of cells grown in the absence of tetracycline (Lane 1; no TauRD expression) were also analyzed in parallel to show background bands derived from endogenous Tau.
- FIGS. 3a and 3b of the priority application show relative levels of soluble/insoluble TauRD oligomers and monomers in compound DC-51-treated TREx293-TauRDWT cell lysates by quantitative densitometric analysis of the Western blots shown in FIGS. 1&2 of the priority application (U.S. Pat. No. 8,455,867).
- FIGS. 4a and 4b of the priority application show relative levels of soluble/insoluble TauRD oligomers and monomers in compound DC-51-W3-treated TREx293-TauRDWT cell lysates by quantitative densitometric analysis of the Western blots shown in FIGS. 1&2 of the priority application (U.S. Pat. No. 8,455,867).
- FIGS. 5a and 5b of the priority application show relative levels of soluble/insoluble TauRD oligomers and monomers in compound DC-51-W4-treated TREx293-TauRDWT cell lysates by quantitative densitometric analysis of the Western blots shown in FIGS. 1&2 of the priority application (U.S. Pat. No. 8,455,867).
- the compounds of this invention modulate tau aggregation and thus potentially are suitable for alleviating tauopathies.
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Abstract
Description
where:
R is a C1-C10 alkylene group, in which, when the number of carbon atoms is at least 2, there are optionally 1 or 2 non-adjacent double bonds; 1 to 3 non-adjacent methylene groups are optionally replaced by NR′ (where R′ is H, alkyl, or acyl), O, or S; and 1 or 2 methylene groups are optionally replaced by a carbonyl or hydroxymethylene group; and
(2) the compounds that are:
3,4,3′,4′-tetrahydroxybenzoin (compound DC-001); 3,4,3′,4′-tetrahydroxydesoxybenzoin (compound DC-002); 3,4,3′,4′-tetrahydroxydiphenylmethane (compound DC-003); 1,2-bis(3,4-dihydroxyphenyl)ethane (compound DC-004); 1,3-bis(3,4-dihydroxyphenyl)propane (compound DC-005); 3,4,3′,4′-tetrahydroxychalcone (compound DC-006); 3,5-bis(3,4-dihydroxyphenyl)-1-methyl-2-pyrazoline (compound DC-007); 4,6-bis(3,4-dihydroxyphenyl)-3-cyano-2-methylpyridine (compound DC-008); 1,4-bis(3,4-dihydroxybenzyl)piperazine (compound DC-009); N,N′-bis(3,4-dihydroxybenzyl)-N,N′-dimethylethylenediamine (compound DC-0010); 2,5-bis(3,4-dihydroxybenzyl)-2,5-diaza[2.2.1]bicycloheptane (compound DC-0011); N,N′-bis(3,4-dihydroxybenzyl)-trans-1,2-diaminocyclohexane (compound DC-0012); N,N′-bis(3,4-dihydroxybenzyl)-trans-1,4-diaminocyclohexane (compound DC-0013); N,N′-bis(3,4-dihydroxybenzyl)-cis-1,3-bis(aminomethyl)cyclohexane (compound DC-0014); N-(3,4-dihydroxybenzyl)proline 3,4-dihydroxybenzylamide (compound DC-0015); 2-(3,4-dihydroxybenzyl)isoquinoline-3-carboxylic acid 3,4-dihydroxyphenethylamide (compound DC-0016); 2,6-bis(3,4-dihydroxybenzyl)-cyclohexanone (compound DC-0017); 3,5-bis(3,4-dihydroxybenzyl)-1-methyl-4-piperidinone (compound DC-(0018); 2,4-bis(3,4-dihydroxybenzyl)-3-tropinone (compound DC-0019); tris-(3,4-dihydroxybenzyl)methane (compound DC-0020); α-(3,4-dihydroxybenzamido)-3,4-dihydroxycinnamic acid 3,4-dihydroxybenzyl amide (compound DC-0021); 4-(3,4-dihydroxybenzylaminomethylene)-2-(3,4-dihydroxyphenyl)oxazolin-5-one (compound DC-0022); 1,4-bis(3,4-dihydroxybenzoyl)piperazine (compound DC-0023); N,N′-bis(3,4-dihydroxybenzoyl)-N,N′-dimethylethylenediamine (compound DC-0024); 2,5-bis(3,4-dihydroxybenzoyl)-2,5-diaza[2.2.1]bicycloheptane (compound DC-0025); N,N′-bis(3,4-dihydroxybenzoyl)-trans-1,2-diaminocyclohexane (compound DC-0026); N,N′-bis(3,4-dihydroxybenzoyl)-cis-1,3-bis(aminomethyl)cyclohexane (compound DC-0027); 3,6-bis(3,4-dihydroxybenzyl)-2,5-diketopiperazine (compound DC-0028); 3,6-bis(3,4-dihydroxybenzylidene)-1,4-dimethyl-2,5-diketopiperazine (compound DC-0029); N-(3,4-dihydroxyphenylacetyl)proline 3,4-dihydroxyanilide (compound DC-0030); 2,3-bis(3,4-dihydroxyphenyl)butane (compound DC-0031); 1,3-bis(3,4-dihydroxybenzyl)benzene (compound DC-0032); 1,4-bis(3,4-dihydroxybenzyl)benzene (compound DC-0033); 2,6-bis(3,4-dihydroxybenzyl)pyridine (compound DC-0034); 2,5-bis(3,4-dihydroxybenzyl)thiophene (compound DC-0035); 2,3-bis(3,4-dihydroxybenzyl)thiophene (compound DC-0036); 1,2-bis(3,4-dihydroxyphenyl)cyclohexane (compound DC-0037); 1,4-bis(3,4-dihydroxyphenyl)cyclohexane (compound DC-0038); 3,7-bis(3,4-dihydroxyphenyl)bicyclo[3.3.0]octane (compound DC-0039); 2,3-bis(3,4-dihydroxyphenyl)-1,7,7-trimethylbicyclo[2.2.1]heptane (compound DC-0040); 1,2-bis(3,4-dihydroxyphenoxy)ethane (compound DC-0041); 1,3-bis(3,4-dihydroxyphenoxy)propane (compound DC-0042); trans-1,2-bis(3,4-dihydroxyphenoxy)-cyclopentane (compound DC-0043); N-(3,4-dihydroxybenzyl)-3-(3,4-dihydroxyphenoxy)-2-hydroxypropylamine (compound DC-0044); 3,4-dihydroxyphenoxyacetic acid 3,4-dihydroxyanilide (compound DC-0045); 3,4-dihydroxyphenoxyacetic acid 3,4-dihydroxybenzylamide (compound DC-0046); 3,4-dihydroxyphenoxyacetic acid 3,4-dihydroxyphenethylamide (compound DC-0047); 3,4-dihydroxybenzoic acid p-(3,4-dihydroxyphenoxy)anilide (compound DC-0048); 3,4-dihydroxybenzoic acid o-(3,4-dihydroxyphenoxy)anilide (compound DC-0049); 2,6-bis(3,4-dihydroxyphenoxy)pyridine (compound DC-0050), 3,4-dihydroxybenzoic acid 3,4-dihydroxyanilide (compound DC-0051); 3,4-dihydroxybenzoic acid 3,4-dihydroxybenzylamide (compound DC-0052); 3,4-dihydroxybenzoic acid 3,4-dihydroxyphenethylamide (compound DC-0053); 3,4-dihydroxyphenylacetic acid 3,4-dihydroxyanilide (compound DC-0054); 3,4-dihydroxyphenylacetic acid 3,4-dihydroxybenzylamide (compound DC-0055); 3,4-dihydroxyphenylacetic acid 3,4-dihydroxyphenethylamide (compound DC-0056); 3-(3,4-dihydroxyphenyl)propionic acid 3,4-dihydroxyanilide (compound DC-0057); 3-(3,4-dihydroxyphenyl) propionic acid 3,4-dihydroxybenzylamide (compound DC-0058); 3-(3,4-dihydroxyphenyl)propionic acid 3,4-dihydroxyphenethylamide (compound DC-0059); 3,4-dihydroxycinnamic acid 3,4-dihydroxyanilide (compound DC-0060); 3,4-dihydroxycinnamic acid 3,4-dihydroxybenzylamide (compound DC-0061); 3,4-dihydroxycinnamic acid 3,4-dihydroxyphenethylamide (compound DC-0062); oxalic acid bis(3,4-dihydroxyanilide) (compound DC-0063); oxalic acid bis(3,4-dihydroxybenzylamide) (compound DC-0064); oxalic acid bis(3,4-dihydroxyphenethylamide) (compound DC-0065); succinic acid bis(3,4-dihydroxyanilide) (compound DC-0066); succinic acid bis(3,4-dihydroxybenzylamide) (compound DC-0067); succinic acid bis(3,4-dihydroxyphenethylamide) (compound DC-0068); maleic acid bis(3,4-dihydroxyanilide) (compound DC-0069); maleic acid bis(3,4-dihydroxybenzylamide) (compound DC-0070); fumaric acid bis(3,4-dihydroxyanilide) (compound DC-0071); fumaric acid bis(3,4-dihydroxybenzylamide) (compound DC-0072); bis(3,4-dihydroxybenzyl)amine (compound DC-0073); N-(3,4-dihydroxybenzyl)-3,4-dihydroxyphenethylamine (compound DC-0074); tris(3,4-dihydroxybenzyl)amine (compound DC-0075); 1,3-bis(3,4-dihydroxyphenyl)urea (compound DC-0076); 1-(3,4-dihydroxyphenyl)-3-(3,4-dihydroxybenzyl)urea (compound DC-0077); 1-(3,4-dihydroxyphenyl)-3-(3,4-dihydroxyphenethyl)urea (compound DC-0078); 3-deoxy-3-(3,4-dihydroxybenzyl)aminoepicatechin (compound DC-0079); 3-deoxy-3-(3,4-dihydroxyphenethyl)aminoepicatechin (compound DC-0080); 2,3,6,7-tetrahydroxy-9,10-epoxy-9,10-dihydroacridine (compound DC-0081); 10-aminoanthracene-1,2,7,8-tetraol (compound DC-0082); acridine-1,2,6,7-tetraol (compound DC-0083); phenoxazine-2,3,7,8,10-pentaol (compound DC-0084); dibenzo[c,f][2,7]napthyridine-2,3,10,11-tetraol (compound DC-0085); and 6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2,10,11-triol (compound DC-0086);
(3) the methylenedioxy analogs and pharmaceutically acceptable esters of compounds of (1) and (2); and
(4) the pharmaceutically acceptable salts of the compounds of (1) to (3).
where:
R1 and R2, and R3 and R4 are hydroxyl groups independently positioned at one of the positions selected from the group consisting of 2,3; 2,4; 2,5; 2,6; 3,5; 3,6; 4,5; 4,6 and 5,6, and R is selected from a sulfonamide, heteroaryl, tricycloalkyl and —C(I)NR′ where R′ is selected from H or CH3 or pharmaceutically acceptable esters or salts thereof and compounds;
where:
R is a C1-C10 alkylene group, in which, when the number of carbon atoms is at least 2, there are optionally 1 or 2 non-adjacent double bonds; 1 to 3 non-adjacent methylene groups are optionally replaced by NR′ (where R′ is H, alkyl, or acyl), O, or S; and 1 or 2 methylene groups are optionally replaced by a carbonyl or hydroxymethylene group; and
(2) the compounds that are:
3,4,3′,4′-tetrahydroxybenzoin (compound DC-001); 3,4,3′,4′-tetrahydroxydesoxybenzoin (compound DC-002); 3,4,3′,4′-tetrahydroxydiphenylmethane (compound DC-003); 1,2-bis(3,4-dihydroxyphenyl)ethane (compound DC-004); 1,3-bis(3,4-dihydroxyphenyl)propane (compound DC-005); 3,4,3′,4′-tetrahydroxychalcone (compound DC-006); 3,5-bis(3,4-dihydroxyphenyl)-1-methyl-2-pyrazoline (compound DC-007); 4,6-bis(3,4-dihydroxyphenyl)-3-cyano-2-methylpyridine (compound DC-008); 1,4-bis(3,4-dihydroxybenzyl)piperazine (compound DC-009); N,N′-bis(3,4-dihydroxybenzyl)-N,N′-dimethylethylenediamine (compound DC-0010); 2,5-bis(3,4-dihydroxybenzyl)-2,5-diaza[2.2.1]bicycloheptane (compound DC-0011); N,N′-bis(3,4-dihydroxybenzyl)-trans-1,2-diaminocyclohexane (compound DC-0012); N,N′-bis(3,4-dihydroxybenzyl)-trans-1,4-diaminocyclohexane (compound DC-0013); N,N′-bis(3,4-dihydroxybenzyl)-cis-1,3-bis(aminomethyl)cyclohexane (compound DC-0014); N-(3,4-dihydroxybenzyl)proline 3,4-dihydroxybenzylamide (compound DC-0015); 2-(3,4-dihydroxybenzyl)isoquinoline-3-carboxylic acid 3,4-dihydroxyphenethylamide (compound DC-0016); 2,6-bis(3,4-dihydroxybenzyl)-cyclohexanone (compound DC-0017); 3,5-bis(3,4-dihydroxybenzyl)-1-methyl-4-piperidinone (compound DC-0018); 2,4-bis(3,4-dihydroxybenzyl)-3-tropinone (compound DC-0019); tris-(3,4-dihydroxybenzyl)methane (compound DC-0020); α-(3,4-dihydroxybenzamido)-3,4-dihydroxycinnamic acid 3,4-dihydroxybenzyl amide (compound DC-0021); 4-(3,4-dihydroxybenzylaminomethylene)-2-(3,4-dihydroxyphenyl)oxazolin-5-one (compound DC-0022); 1,4-bis(3,4-dihydroxybenzoyl)piperazine (compound DC-0023); N,N′-bis(3,4-dihydroxybenzoyl)-N,N′-dimethylethylenediamine (compound DC-0024); 2,5-bis(3,4-dihydroxybenzoyl)-2,5-diaza[2.2.1]bicycloheptane (compound DC-0025); N,N′-bis(3,4-dihydroxybenzoyl)-trans-1,2-diaminocyclohexane (compound DC-0026); N,N′-bis(3,4-dihydroxybenzoyl)-cis-1,3-bis(aminomethyl)cyclohexane (compound DC-0027); 3,6-bis(3,4-dihydroxybenzyl)-2,5-diketopiperazine (compound DC-0028); 3,6-bis(3,4-dihydroxybenzylidene)-1,4-dimethyl-2,5-diketopiperazine (compound DC-0029); N-(3,4-dihydroxyphenylacetyl)proline 3,4-dihydroxyanilide (compound DC-0030); 2,3-bis(3,4-dihydroxyphenyl)butane (compound DC-0031); 1,3-bis(3,4-dihydroxybenzyl)benzene (compound DC-0032); 1,4-bis(3,4-dihydroxybenzyl)benzene (compound DC-0033); 2,6-bis(3,4-dihydroxybenzyl)pyridine (compound DC-0034); 2,5-bis(3,4-dihydroxybenzyl)thiophene (compound DC-0035); 2,3-bis(3,4-dihydroxybenzyl)thiophene (compound DC-0036); 1,2-bis(3,4-dihydroxyphenyl)cyclohexane (compound DC-0037); 1,4-bis(3,4-dihydroxyphenyl)cyclohexane (compound DC-0038); 3,7-bis(3,4-dihydroxyphenyl)bicyclo[3.3.0]octane (compound DC-0039); 2,3-bis(3,4-dihydroxyphenyl)-1,7,7-trimethylbicyclo[2.2.1]heptane (compound DC-0040); 1,2-bis(3,4-dihydroxyphenoxy)ethane (compound DC-0041); 1,3-bis(3,4-dihydroxyphenoxy)propane (compound DC-0042); trans-1,2-bis(3,4-dihydroxyphenoxy)-cyclopentane (compound DC-0043); N-(3,4-dihydroxybenzyl)-3-(3,4-dihydroxyphenoxy)-2-hydroxypropylamine (compound DC-0044); 3,4-dihydroxyphenoxyacetic acid 3,4-dihydroxyanilide (compound DC-0045); 3,4-dihydroxyphenoxyacetic acid 3,4-dihydroxybenzylamide (compound DC-0046); 3,4-dihydroxyphenoxyacetic acid 3,4-dihydroxyphenethylamide (compound DC-0047); 3,4-dihydroxybenzoic acid p-(3,4-dihydroxyphenoxy)anilide (compound DC-0048); 3,4-dihydroxybenzoic acid o-(3,4-dihydroxyphenoxy)anilide (compound DC-0049); 2,6-bis(3,4-dihydroxyphenoxy)pyridine (compound DC-0050), 3,4-dihydroxybenzoic acid 3,4-dihydroxyanilide (compound DC-0051); 3,4-dihydroxybenzoic acid 3,4-dihydroxybenzylamide (compound DC-0052); 3,4-dihydroxybenzoic acid 3,4-dihydroxyphenethylamide (compound DC-0053); 3,4-dihydroxyphenylacetic acid 3,4-dihydroxyanilide (compound DC-0054); 3,4-dihydroxyphenylacetic acid 3,4-dihydroxybenzylamide (compound DC-0055); 3,4-dihydroxyphenylacetic acid 3,4-dihydroxyphenethylamide (compound DC-0056); 3-(3,4-dihydroxyphenyl)propionic acid 3,4-dihydroxyanilide (compound DC-0057); 3-(3,4-dihydroxyphenyl) propionic acid 3,4-dihydroxybenzylamide (compound DC-0058); 3-(3,4-dihydroxyphenyl)propionic acid 3,4-dihydroxyphenethylamide (compound DC-0059); 3,4-dihydroxycinnamic acid 3,4-dihydroxyanilide (compound DC-0060); 3,4-dihydroxycinnamic acid 3,4-dihydroxybenzylamide (compound DC-0061); 3,4-dihydroxycinnamic acid 3,4-dihydroxyphenethylamide (compound DC-0062); oxalic acid bis(3,4-dihydroxyanilide) (compound DC-0063); oxalic acid bis(3,4-dihydroxybenzylamide) (compound DC-0064); oxalic acid bis(3,4-dihydroxyphenethylamide) (compound DC-0065); succinic acid bis(3,4-dihydroxyanilide) (compound DC-0066); succinic acid bis(3,4-dihydroxybenzylamide) (compound DC-0067); succinic acid bis(3,4-dihydroxyphenethylamide) (compound DC-0068); maleic acid bis(3,4-dihydroxyanilide) (compound DC-0069); maleic acid bis(3,4-dihydroxybenzylamide) (compound DC-0070); fumaric acid bis(3,4-dihydroxyanilide) (compound DC-0071); fumaric acid bis(3,4-dihydroxybenzylamide) (compound DC-0072); bis(3,4-dihydroxybenzyl)amine (compound DC-0073); N-(3,4-dihydroxybenzyl)-3,4-dihydroxyphenethylamine (compound DC-0074); tris(3,4-dihydroxybenzyl)amine (compound DC-0075); 1,3-bis(3,4-dihydroxyphenyl)urea (compound DC-0076); 1-(3,4-dihydroxyphenyl)-3-(3,4-dihydroxybenzyl)urea (compound DC-0077); 1-(3,4-dihydroxyphenyl)-3-(3,4-dihydroxyphenethyl)urea (compound DC-0078); 3-deoxy-3-(3,4-dihydroxybenzyl)aminoepicatechin (compound DC-0079); 3-deoxy-3-(3,4-dihydroxyphenethyl)aminoepicatechin (compound DC-0080); 2,3,6,7-tetrahydroxy-9,10-epoxy-9,10-dihydroacridine (compound DC-0081); 10-aminoanthracene-1,2,7,8-tetraol (compound DC-0082); acridine-1,2,6,7-tetraol (compound DC-0083); phenoxazine-2,3,7,8,10-pentaol (compound DC-0084); dibenzo[c,f][2,7]napthyridine-2,3,10,11-tetraol (compound DC-0085); and 6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2,10,11-triol (compound DC-0086);
(3) the methylenedioxy analogs and pharmaceutically acceptable esters of compounds of (1) and (2); and
(4) the pharmaceutically acceptable salts of the compounds of (1) to (3).
where:
R1 and R2, and R3 and R4 are hydroxyl groups independently positioned at one of the positions selected from the group consisting of 2,3; 2,4; 2,5; 2,6; 3,5; 3,6; 4,5; 4,6 and 5,6, and
R is selected from a sulfonamide, heteroaryl, tricycloalkyl and —C(O)NR′ where R′ is selected from H or CH3 or pharmaceutically acceptable esters or salts thereof.
TABLE 1 |
Thioflavin T fluorometry data - dissolution/disruption/inhibition |
of Tau aggregates |
% dissolution/disruption/inhibition Tau (result ± S.D.) |
at Tau:test compound wt/wt ratio |
Test Compound # | 1:1 | 1:0.1 | 1:0.01 | 1:0.001 |
Negative control | 15.4 ± 3.97 | 11.5 ± 2.85 | 11.2 ± 3.47 | 11.1 ± 1.98 |
DC-003 | 91.2 ± 2.59 | 89.2 ± 1.96 | 54.1 ± 2.62 | 17.0 ± 2.49 |
DC-004 | 93.5 ± 4.42 | 92.8 ± 2.59 | 68.0 ± 1.71 | 19.3 ± 0.00 |
DC-0021 | 94.8 ± 2.59 | 75.2 ± 2.04 | 31.7 ± 5.45 | 9.8 ± 2.95 |
DC-0023 | 71.3 ± 2.04 | 33.4 ± 1.49 | 15.2 ± 2.49 | 11.4 ± 1.14 |
DC-0051 | 96.1 ± 0.56 | 87.9 ± 5.03 | 51.5 ± 5.51 | 11.8 ± 4.67 |
DC-0051-C | 92.2 ± 2.04 | 81.7 ± 4.07 | 38.6 ± 6.59 | 5.2 ± 6.04 |
DC-0063 | 77.8 ± 1.13 | 34.7 ± 1.69 | 16.5 ± 2.49 | 11.8 ± 8.06 |
DC-0076 | 94.1 ± 2.99 | 91.2 ± 0.56 | 54.1 ± 2.62 | 17.4 ± 4.88 |
DC-51-OH1 | 100.0 ± 1.62 | 90.0 ± 2.14 | 58.0 ± 2.05 | 13.2 ± 5.38 |
DC-51-OH2 | 100.0 ± 3.38 | 88.1 ± 2.85 | 43.7 ± 3.38 | 10.6 ± 5.36 |
DC-51-OH3 | 100.0 ± 2.94 | 86.0 ± 5.69 | 61.5 ± 2.05 | 12.4 ± 5.38 |
DC-51-CH3 | 100.0 ± 0.89 | 90.0 ± 2.43 | 59.4 ± 2.61 | 13.0 ± 5.06 |
DC-51-W1 | 100.0 ± 1.55 | 87.3 ± 1.69 | 50.2 ± 4.96 | 16.5 ± 2.48 |
DC-51-W2 | 97.7 ± 1.95 | 92.4 ± 1.23 | 74.0 ± 4.01 | 25.7 ± 4.90 |
DC-51-W3 | 100.0 ± 1.62 | 90.3 ± 2.04 | 37.2 ± 4.96 | 6.0 ± 5.12 |
DC-51-W4 | 100.0 ± 4.32 | 88.9 ± 6.74 | 57.7 ± 24.96 | 11.9 ± 3.28 |
DC-51-W5 | 96.6 ± 2.80 | 91.1 ± 0.81 | 35.2 ± 2.59 | 7.6 ± 3.38 |
Claims (8)
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US15/265,608 US20170008838A1 (en) | 2002-05-31 | 2016-09-14 | Compounds and compositions for use as modulators of tau aggregation and alleviation of tauopathies |
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US43588002P | 2002-12-20 | 2002-12-20 | |
US46310403P | 2003-04-14 | 2003-04-14 | |
US10/452,851 US7514583B2 (en) | 2002-05-31 | 2003-05-30 | Compounds, compositions and methods for the treatment of amyloid diseases and synucleinopathies such as alzheimer's disease, type 2 diabetes, and parkinson's disease |
US144107P | 2007-10-31 | 2007-10-31 | |
US12/244,968 US8829198B2 (en) | 2007-10-31 | 2008-10-03 | Compounds, compositions and methods for the treatment of beta-amyloid diseases and synucleinopathies |
US12/269,017 US20090197965A1 (en) | 2002-05-31 | 2008-11-11 | Compounds, compositions and methods for the treatment of amyloid diseases and synucleinopathies such as alzheimer's disease, type 2 diabetes, and parkinson's disease |
US29900510P | 2010-01-28 | 2010-01-28 | |
US13/010,023 US8455687B2 (en) | 2002-05-31 | 2011-01-20 | Compounds and compositions for use as modulators of tau aggregation and alleviation of tauopathies |
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US13/868,291 Abandoned US20140005240A1 (en) | 2002-05-31 | 2013-07-18 | Compounds and compositions for use as modulators of tau aggregation and alleviation of tauopathies |
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US15/265,608 Abandoned US20170008838A1 (en) | 2002-05-31 | 2016-09-14 | Compounds and compositions for use as modulators of tau aggregation and alleviation of tauopathies |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0324521A2 (en) | 1988-01-11 | 1989-07-19 | Duphar International Research B.V | Method of treating haematologic diseases and pharmaceutical compositions to be used therefor |
US5166180A (en) | 1988-01-11 | 1992-11-24 | Duphar International Research B.V. | Method of treating hematologic diseases and pharmaceutical composition to be used therefor |
US7514583B2 (en) * | 2002-05-31 | 2009-04-07 | Proteotech, Inc. | Compounds, compositions and methods for the treatment of amyloid diseases and synucleinopathies such as alzheimer's disease, type 2 diabetes, and parkinson's disease |
-
2013
- 2013-07-18 US US13/868,291 patent/US20140005240A1/en not_active Abandoned
-
2014
- 2014-06-10 US US14/300,572 patent/US9469605B2/en not_active Expired - Fee Related
-
2016
- 2016-09-14 US US15/265,608 patent/US20170008838A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0324521A2 (en) | 1988-01-11 | 1989-07-19 | Duphar International Research B.V | Method of treating haematologic diseases and pharmaceutical compositions to be used therefor |
US5166180A (en) | 1988-01-11 | 1992-11-24 | Duphar International Research B.V. | Method of treating hematologic diseases and pharmaceutical composition to be used therefor |
US7514583B2 (en) * | 2002-05-31 | 2009-04-07 | Proteotech, Inc. | Compounds, compositions and methods for the treatment of amyloid diseases and synucleinopathies such as alzheimer's disease, type 2 diabetes, and parkinson's disease |
Non-Patent Citations (2)
Title |
---|
Database CAPLUS in STN, Acc. No. 1966:484808, Leader et al., Biochemical Pharmacology (1966), 15(9), pp. 1379-1387 (abstract). * |
Database CAPLUS in STN, Acc. No. 1977:534458, Runge et al. DD 122967 A1 (Nov. 12, 1976) (abstract). * |
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US20170008838A1 (en) | 2017-01-12 |
US20140288183A1 (en) | 2014-09-25 |
US20140005240A1 (en) | 2014-01-02 |
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